The invention relates to prosthetic material that is treated to reduce calcification. More particularly, the invention relates to prosthetic material which is complexed with slowly released calcification inhibitors.
Bioprostheses, i.e., bioprosthetic devices, are used to repair or replace damaged or diseased organs, tissues and other structures in humans and animals. Bioprostheses must be generally biocompatible since they are typically implanted for extended periods of time. Specifically, bioprostheses can include artificial hearts, artificial heart valves, ligament repair material, vessel repair, surgical patches constructed of mammalian tissue and the like. Bioprostheses can be constructed from a combination of natural or synthetic materials.
Calcification, i.e., the deposit of calcium salts especially calcium phosphate (hydroxyapatite), occurs in and on some materials used in the production of implantable bioprostheses. This affects the performance and structural integrity of medical devices constructed from these biomaterials, especially over extended periods of time. For example, calcification is the primary cause of clinical failure of bioprosthetic heart valves made from porcine aortic valves or bovine pericardium. Calcification also significantly affects the performance of bioprostheses constructed from synthetic materials, such as polyurethane.
The importance of bioprosthetic animal heart valves as replacements for damaged human heart valves has resulted in a considerable amount of attention directed to the effects of calcification on these xenotransplants. Bioprosthetic heart valves from natural materials were introduced in the early 1960's and are typically derived from pig aortic valves or are manufactured from other biological materials such as bovine pericardium. Xenograft heart valves are typically fixed with glutaraldehyde prior to implantation to reduce the possibility of immunological rejection. Glutaraldehyde reacts to form covalent bonds with free amino groups in proteins, thereby chemically crosslinking nearby proteins.
Generally, bioprosthetic heart valves begin failing after about seven years following implantation, and few bioprosthetic valves remain functional after 20 years. Replacement of a degenerating valve prosthesis subjects the patient to additional surgical risk, especially in the elderly and in situations of emergency replacement. While failure of bioprostheses is a problem for patients of all ages, it is particularly pronounced in younger patients. Over fifty percent of bioprosthetic valve replacements in patients under the age of 15 fail in less than five years because of calcification.
Similarly, calcification of polyurethane bladders in artificial hearts and of leaflets in polyurethane valves is potentially clinically significant. Other bioprostheses made from natural and/or synthetic materials display clinically significant calcification.
As a result, there is considerable interest in preventing the deposit of calcium on implanted biomaterials, especially heart valves. Research on the prevention of calcification has focused to a considerable extent on the pretreatment of the biomaterial prior to implantation. Detergents (e.g., sodium dodecyl sulfate), toluidine blue or diphosphonates have been used to pretreat tissues in an attempt to decrease calcification by reducing calcium nucleation. These materials tend to wash out of the bioprosthetic material rather rapidly into the body fluids surrounding the implant, limiting their effectiveness.
Another approach to reducing calcification has been to remove at least some of the reactive glutaraldehyde moieties from the tissue by a chemical process. Still other approaches have included development of alternative fixation techniques, since evidence suggests that the fixation process itself contributes to calcification and the corresponding mechanical deterioration. In addition, since nonviable cells present in transplanted tissue are sites for calcium deposition, various processes have been developed to remove cellular material from the collagen--elastin matrix of the tissue prior to implantation.
A significant advance toward reducing calcification of bioprostheses was the determination that Al.sup.+3 cations and other multivalent cations inhibit calcification. Bioprosthetic materials were treated with an acidic, aqueous solution of AlCl.sub.3 prior to implantation. While some of the Al.sup.+3 cations wash away after being removed from the treatment solution, a significant amount of cations remain associated with the treated materials for extended periods of time, presumably due to some type of association of the cations with the bioprosthetic material. It appears that the loading of ions into the material reaches a limiting value.
The associated Al.sup.+3 cations are found to contribute to significant inhibition of the deposit of calcium. Furthermore, this effect persisted over a significant period of time, at least several months in a juvenile animal. Treatment with Fe.sup.+3 salts is observed to produce similar effectiveness in reducing calcification.
It has been proposed that alkaline phosphatase is involved in the calcification of bioprostheses. Calcification seems related to cellular destruction and the corresponding disruption of cellular calcium regulation that maintains low intracellular calcium concentrations due to the pumping of Ca.sup.+2 out of the cell. Cellular damage results from mechanical damage, extreme pH, extreme ionic concentration and/or chemical fixation, such as glutaraldehyde treatment. The cellular damage results in an uncontrolled influx of calcium into the nonviable cells.
Physiologically normal calcification of skeletal and dental tissues and pathological calcification, such as calcification of bioprostheses, have important similarities including the initial deposit of apatitic mineral. These mineral deposits contain calcium and phosphates, and mineral growth takes place at nuclei provided by initial deposits. Nucleation in bone development takes place at structures that have a high concentration of calcium binding phospholipids and high activity of phosphatases, especially alkaline phosphatase. Alkaline phosphatase activity is particularly high in children, which may contribute to the severe calcification problem for bioprostheses implanted into young patients.
Phosphatase activity is found to be inhibited by incubation with AlCl.sub.3 and FeCl.sub.3. This result suggests that the effect of Al.sup.+3 and Fe.sup.+3 cations in reducing calcification is due to the inhibition of the phosphatase activity. Alternatively or in addition, the ions may act by substitution into the hydroxyapatite crystal lattice which could prevent growth by destabilizing the crystal.